With the advent of an aging society, the problem of the medical care of senile citizens has been drawing attention. Above all, senile dementia has become a serious social problem, and many developments have been made in an attempt to provide new pharmaceuticals to cope with the situation. The conventional therapeutic agents for amnesia and dementia have been named obscurely as cerebral circulation-improving agents, cerebral metabolism activator or cerebral function-improving agents according to their action mechanisms. While they are effective for the improvement of peripheral symptoms such as depression, emotional disturbances, abnormal behavior, etc., they do not show definite effects on the central symptoms of dementia, such as memory disorder, disorientation and the like. Thus, the development of pharmaceutical agents which can provide dependable action and effects on these symptoms is desired.
Prolyl endopeptidase; EC, 3.4.21.26 is known to act on peptides containing proline and to specifically cleave the carboxyl side of the proline. Further, this enzyme vasopressin which is presumably concerned with learning and memory process, to decompose and inactivate same.
In view of the foregoing findings, a compound possessing specific inhibitory activity on this enzyme is expected to suppress decomposition and inactivation of vasopressin, etc., thus suggesting a potential application thereof to the treatment and prevention of amnesia and dementia, as a pharmaceutical agent which directly acts on the central symptoms of dementia [see Seikagaku, 55, 831 (1983); FOLIA PHARMACOL. JAPON, 89, 243 (1987); and J. Pharmacobio-Dyn., 10, 730 (1987)]. It is also expected that such a compound suppresses decomposition and inactivation of hormones and neurotransmitters such as TRH, substance P, neurotensin etc., thereby improving various symptoms caused by the decomposition and inactivation of these substances. Recent studies have revealed that beta amyloid protein plays a substantial and important role in the onset of Alzheimer's disease by the neorotoxic action thereof in in vitro and in vivo tests. Based on the hypothesis that prolyl endopeptidase is an enzyme for cleaving out a beta amyloid from an amyloid precursor protein (FEBS Lett., 260, 131-134 (1990)] and the experimental fact that the neurotoxic action of beta amyloid protein is suppressed by substance P [Proc. Natl. Acad. Sci. USA, 88, 7247-7251 (1991)], a prolyl endopeptidase inhibitor is considered to become an effective medicine for Alzheimer's disease.
There have been conventionally attempted to develop prolyl endopeptidase inhibitors and various proline derivatives are described and disclosed in, for example, Japanese Patent Unexamined Publication Nos. 148467/1987, 42475/1989, 6263/1989, 230578/1989 and 28149/1990.